arXiv subjects

Tobias Mütze

Publications and source records attributed to Tobias Mütze.

11 recordsLinked to original sources

arXiv2026

Tipping Point Sensitivity Analysis for Missing Data in Time-to-Event Endpoints: Model-Based and Ad hoc Approaches

Treatment policy estimands are frequently favored by regulators, as they assess the effect of treatment assignment regardless of post-randomization events. Despite best efforts, missing data due to study discontinuation cannot be fully avoided and, for time-to-event endpoints, typically manifests as right censoring. Study discontinuation is often more likely following intercurrent events, particularly when it coincides with treatment discontinuation, raising concerns about violations of the independent censoring assumption. Although the independent censoring assumption is routinely adopted for the main analyses, it may be unrealistic in practice and could lead to biased estimation of the treatment effect under the treatment policy estimand. Tipping-point analyses provide a structured framework to assess the robustness of trial conclusions to departures from the independent censoring assumption. This paper describes and contrasts model-based and two ad hoc tipping point approaches, which involve "landmark" or "percentile sampling" based imputation. We illustrate their application using re-constructed examples based on real clinical trials, highlighting their underlying assumptions and implications for interpretation and clinical plausibility assessments of different tipping point approaches.

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arXiv2026

Covariate Adjustment for the Win Odds: Application to Cardiovascular Outcomes Trials

Covariate adjustment can enhance precision and power in clinical trials, yet its application to the win odds remains unclear. The win odds is an extension of the win ratio that counts ties as half a win for the treatment and the control group, respectively. In their original form, both the win ratio and the win odds rely on comparing each individual from the treatment group to each individual from the control group in a pairwise manner, and count the number of wins, losses, and ties from these pairwise comparisons. A priori, it is not clear how covariate adjustment can be implemented for the win odds. To address this, we establish a connection between the win odds and the marginal probabilistic index, a measure for which covariate adjustment theory is well-developed. Using this connection, we show how covariate adjustment for the win odds is possible, leading to potentially more precise estimators and larger power as compared to the unadjusted win odds. We present the underlying theory for covariate adjustment for the win odds in an accessible way and apply the method on synthetic data based on the CANTOS trial (ClinicalTrials.gov identifier: NCT01327846) characteristics, on a subset of the HF-ACTION trial data (ClinicalTrials.gov identifier: NCT00047437), and on simulated data to study the operating characteristics of the method. We observe that there is indeed a potential gain in power when the win odds is adjusted for baseline covariates if the baseline covariates are prognostic for the outcome. This comes at the cost of a slight inflation of the type I error rate for small sample sizes.

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arXiv2026

Estimands and the Choice of Non-Inferiority Margin under ICH E9(R1)

Since the release of the ICH E9(R1) addendum on estimands, its application in non-inferiority trials has received far less attention than in superiority settings. A key conclusion from Lynggaard et al. was that the "choice of non-inferiority margin must reflect the chosen estimand." However, current regulatory guidance predates ICH E9(R1) and therefore does not reflect how the estimand influences the historical evidence and constancy assumption (assay sensitivity) used to derive the non-inferiority margin. This paper investigates the degree to which the non-inferiority margin depends on the estimand. Using simulated patient journeys in a weight-management setting, we illustrate how different intercurrent event strategies and variations in the intercurrent event frequency affect the estimand, and consequently the estimated treatment effect. These results emphasize that the historical treatment effect of the reference treatment versus placebo, and thus the margin $M_{1}$, is specific to an estimand and may differ even when trials formally target similar questions. We further illustrate the process of determining the non-inferiority margin using two examples in non-inferiority trials for a new theoretical weight management treatment. In the first example, we focus on the setting where the historical clinical trials use the estimand framework highlighting that even when they include the estimand framework, determining the non-inferiority margin can be challenging in case the historical trials target an estimand different from the one in the planned study. A second example highlights challenges when historical trials did not employ the estimand framework and the targeted estimand cannot be fully reconstructed.

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arXiv2024

A studentized permutation test in group sequential designs

In group sequential designs, where several data looks are conducted for early stopping, we generally assume the vector of test statistics from the sequential analyses follows (at least approximately or asymptotially) a multivariate normal distribution. However, it is well-known that test statistics for which an asymptotic distribution is derived may suffer from poor small sample approximation. This might become even worse with an increasing number of data looks. The aim of this paper is to improve the small sample behaviour of group sequential designs while maintaining the same asymptotic properties as classical group sequential designs. This improvement is achieved through the application of a modified permutation test. In particular, this paper shows that the permutation distribution approximates the distribution of the test statistics not only under the null hypothesis but also under the alternative hypothesis, resulting in an asymptotically valid permutation test. An extensive simulation study shows that the proposed permutation test better controls the Type I error rate than its competitors in the case of small sample sizes.

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arXiv2024

Estimation methods for estimands using the treatment policy strategy; a simulation study based on the PIONEER 1 Trial

Estimands using the treatment policy strategy for addressing intercurrent events are common in Phase III clinical trials. One estimation approach for this strategy is retrieved dropout whereby observed data following an intercurrent event are used to multiply impute missing data. However, such methods have had issues with variance inflation and model fitting due to data sparsity. This paper introduces likelihood-based versions of these approaches, investigating and comparing their statistical properties to the existing retrieved dropout approaches, simpler analysis models and reference-based multiple imputation. We use a simulation based upon the data from the PIONEER 1 Phase III clinical trial in Type II diabetics to present complex and relevant estimation challenges. The likelihood-based methods display similar statistical properties to their multiple imputation equivalents, but all retrieved dropout approaches suffer from high variance. Retrieved dropout approaches appear less biased than reference-based approaches, resulting in a bias-variance trade-off, but we conclude that the large degree of variance inflation is often more problematic than the bias. Therefore, only the simpler retrieved dropout models appear appropriate as a primary analysis in a clinical trial, and only where it is believed most data following intercurrent events will be observed. The jump-to-reference approach may represent a more promising estimation approach for symptomatic treatments due to its relatively high power and ability to fit in the presence of much missing data, despite its strong assumptions and tendency towards conservative bias. More research is needed to further develop how to estimate the treatment effect for a treatment policy strategy.

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arXiv2020

Data monitoring committees for clinical trials evaluating treatments of COVID-19

The first cases of coronavirus disease 2019 (COVID-19) were reported in December 2019 and the outbreak of SARS-CoV-2 was declared a pandemic in March 2020 by the World Health Organization. This sparked a plethora of investigations into diagnostics and vaccination for SARS-CoV-2, as well as treatments for COVID-19. Since COVID-19 is a severe disease associated with a high mortality, clinical trials in this disease should be monitored by a data monitoring committee (DMC), also known as data safety monitoring board (DSMB). DMCs in this indication face a number of challenges including fast recruitment requiring an unusually high frequency of safety reviews, more frequent use of complex designs and virtually no prior experience with the disease. In this paper, we provide a perspective on the work of DMCs for clinical trials of treatments for COVID-19. More specifically, we discuss organizational aspects of setting up and running DMCs for COVID-19 trials, in particular for trials with more complex designs such as platform trials or adaptive designs. Furthermore, statistical aspects of monitoring clinical trials of treatments for COVID-19 are considered. Some recommendations are made regarding the presentation of the data, stopping rules for safety monitoring and the use of external data. The proposed stopping boundaries are assessed in a simulation study motivated by clinical trials in COVID-19.

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arXiv2019

Blinded continuous information monitoring of recurrent event endpoints with time trends in clinical trials

Blinded sample size re-estimation and information monitoring based on blinded data has been suggested to mitigate risks due to planning uncertainties regarding nuisance parameters. Motivated by a randomized controlled trial in pediatric multiple sclerosis (MS), a continuous monitoring procedure for overdispersed count data was proposed recently. However, this procedure assumed constant event rates, an assumption often not met in practice. Here we extend the procedure to accommodate time trends in the event rates considering two blinded approaches: (a) the mixture approach modeling the number of events by a mixture of two negative binomial distributions, and (b) the lumping approach approximating the marginal distribution of the event counts by a negative binomial distribution. Through simulations the operating characteristics of the proposed procedures are investigated under decreasing event rates. We find that the type I error rate is not inflated relevantly by either of the monitoring procedures, with the exception of strong time dependencies where the procedure assuming constant rates exhibits some inflation. Furthermore, the procedure accommodating time trends has generally favorable power properties compared to the procedure based on constant rates which stops often too late. The proposed method is illustrated by the clinical trial in pediatric MS.

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arXiv2019

Sample size re-estimation incorporating prior information on a nuisance parameter

Prior information is often incorporated informally when planning a clinical trial. Here, we present an approach on how to incorporate prior information, such as data from historical clinical trials, into the nuisance parameter based sample size re-estimation in a design with an internal pilot study. We focus on trials with continuous endpoints in which the outcome variance is the nuisance parameter. For planning and analyzing the trial frequentist methods are considered. Moreover, the external information on the variance is summarized by the Bayesian meta-analytic-predictive (MAP) approach. To incorporate external information into the sample size re-estimation, we propose to update the MAP prior based on the results of the internal pilot study and to re-estimate the sample size using an estimator from the posterior. By means of a simulation study, we compare the operating characteristics such as power and sample size distribution of the proposed procedure with the traditional sample size re-estimation approach which uses the pooled variance estimator. The simulation study shows that, if no prior-data conflict is present, incorporating external information into the sample size re-estimation improves the operating characteristics compared to the traditional approach. In the case of a prior-data conflict, that is when the variance of the ongoing clinical trial is unequal to the prior location, the performance of the traditional sample size re-estimation procedure is in general superior, even when the prior information is robustified. When considering to include prior information in sample size re-estimation, the potential gains should be balanced against the risks.

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arXiv2019

Group sequential designs for negative binomial outcomes

Count data and recurrent events in clinical trials, such as the number of lesions in magnetic resonance imaging in multiple sclerosis, the number of relapses in multiple sclerosis, the number of hospitalizations in heart failure, and the number of exacerbations in asthma or in chronic obstructive pulmonary disease (COPD) are often modeled by negative binomial distributions. In this manuscript we study planning and analyzing clinical trials with group sequential designs for negative binomial outcomes. We propose a group sequential testing procedure for negative binomial outcomes based on Wald statistics using maximum likelihood estimators. The asymptotic distribution of the proposed group sequential tests statistics are derived. The finite sample size properties of the proposed group sequential test for negative binomial outcomes and the methods for planning the respective clinical trials are assessed in a simulation study. The simulation scenarios are motivated by clinical trials in chronic heart failure and relapsing multiple sclerosis, which cover a wide range of practically relevant settings. Our research assures that the asymptotic normal theory of group sequential designs can be applied to negative binomial outcomes when the hypotheses are tested using Wald statistics and maximum likelihood estimators. We also propose two methods, one based on Student's t-distribution and one based on resampling, to improve type I error rate control in small samples. The statistical methods studied in this manuscript are implemented in the R package \textit{gscounts}, which is available for download on the Comprehensive R Archive Network (CRAN).

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arXiv2017

Blinded sample size re-estimation in three-arm trials with 'gold standard' design

The sample size of a clinical trial relies on information about nuisance parameters such as the outcome variance. When no or only limited information is available, it has been proposed to include an internal pilot study in the design of the trial. Based on the results of the internal pilot study, the initially planned sample size can be adjusted. In this paper, we study blinded sample size re-estimation in the 'gold standard' design for normally distributed outcomes. The 'gold standard' design is a three-arm clinical trial design which includes an active and a placebo control in addition to an experimental treatment. We compare several sample size re-estimation procedures in a simulation study assessing operating characteristics including power and type I error. We find that sample size re-estimation based on the popular one-sample variance estimator results in overpowered trials. Moreover, sample size re-estimation based on unbiased variance estimators such as the Xing-Ganju variance estimator results in underpowered trials, as it is expected since an overestimation of the variance and thus the sample size is in general required for the re-estimation procedure to eventually meet the target power. Moreover, we propose an inflation factor for the sample size re-estimation with the Xing-Ganju variance estimator and show that this approach results in adequately powered trials. Due to favorable features of Xing-Ganju variance estimator such as unbiasedness and a distribution independent of the group means, the inflation factor does not depend on the nuisance parameter and, therefore, can be calculated prior to a trial.

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arXiv2016

A studentized permutation test for three-arm trials in the 'gold standard' design

The 'gold standard' design for three-arm trials refers to trials with an active control and a placebo control in addition to the experimental treatment group. This trial design is recommended when being ethically justifiable and it allows the simultaneous comparison of experimental treatment, active control, and placebo. Parametric testing methods have been studied plentifully over the past years. However, these methods often tend to be liberal or conservative when distributional assumptions are not met particularly with small sample sizes. In this article, we introduce a studentized permutation test for testing non-inferiority and superiority of the experimental treatment compared to the active control in three-arm trials in the `gold standard' design. The performance of the studentized permutation test for finite sample sizes is assessed in a Monte-Carlo simulation study under various parameter constellations. Emphasis is put on whether the studentized permutation test meets the target significance level. For comparison purposes, commonly used Wald-type tests are included in the simulation study. The simulation study shows that the presented studentized permutation test for assessing non-inferiority in three-arm trials in the 'gold standard' design outperforms its competitors for count data. The methods discussed in this paper are implemented in the R package ThreeArmedTrials which is available on the comprehensive R archive network (CRAN).

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